Obesity, hyperlipidemia, and insulin resistance are common forerunners of type 2 diabetes mellitus. The human winged helix/forkhead transcription factor gene FOXC2 has been identified as a key regulator of adipocyte metabolism (Cederberg, A. et al. (2001) Cell 106:563–573). Increased FOXC2 expression, in adipocytes, has a pleiotropic effect on gene expression, which leads to a lean and insulin sensitive phenotype. FOXC2 affects adipocyte metabolism by increasing the sensitivity of the beta-adrenergic-cAMP-protein kinase A (PKA) signaling pathway through alteration of adipocyte PKA holoenzyme composition. Increased FOXC2 levels, induced by high fat diet, seem to counteract most of the symptoms associated with obesity, including hypertriglyceridemia and diet-induced insulin resistance; a likely consequence hereof would be protection against type 2 diabetes.
The nucleotide and amino acid sequences of the human FOXC2 protein (SEQ ID NO:1), also known as FKHL14, FREAC-11, or S12, as well as the corresponding mouse mesenchyme forkhead-1 (MFH-1) protein, are known in the art, see Miura, N. et al. (1993) FEBS letters 326: 171–176; Miura, N. et al. (1997) Genomics 41: 489–492; WO 98/54216 and WO 01/60853.
Various mechanisms have been proposed for how FOXC2 function to regulate gene expression. One possibility is that FOXC2 interact with factors that are downstream of the Notch-Delta signaling pathway (Kume, T. et al. (2001) Genes & Development 15:2470–2482). For example, Groucho proteins form transcription repression complexes with bHLH transcriptions factors. It has been shown that Groucho can bind to two FOX proteins, FOXG1 and FOXA2 (Wang, J. -C. et al. (2001) J. Biol. Chem. 275: 18418–18423; Yao, J. et al. (2001) Mol. Cell. Biol. 21:1962–1972), and it was suggested that similar kinds of interactions may occur with FOXC proteins (Kume et al., supra). However, an interaction between the FOXC2 protein and Groucho has not previously been demonstrated. Further, interactions of FOXC2 with any of the proteins designated p621, NOLP, Heat Shock Cognate Protein-71 (HSC71), FTP3, CLH1, or Kinase A Anchor Protein 84/149 (AKAP) have not been previously described.